Contributed by Robert H. Austin, June 26, 2015 (sent for review May 27, 2014; reviewed by Eshel Ben-Jacob2 and Michael W. Deem)
There are two broad components of information dynamics in cancer evolution. One involves permanent changes in which genes are subject to gain or loss-of-function substitutions. This is well established and the main focus of cancer research. The other component is the information in the human genome and preservation of that content. The cancer cell potentially has access to all of this and can upregulate or downregulate any number of strategies used for survival and proliferation during embryogenesis, development, and normal adaptation to environmental stresses. We suggest that nonsubstituted genes may be critical targets for chemotherapy; these nonmutated genes may be the most fundamental ones for preservation of cancer cell fitness, especially if their expression level changes.
We use a microfabricated ecology with a doxorubicin gradient and population fragmentation to produce a strong Darwinian selective pressure that drives forward the rapid emergence of doxorubicin resistance in multiple myeloma (MM) cancer cells. RNA sequencing of the resistant cells was used to examine (i) emergence of genes with high de novo substitution densities (i.e., hot genes) and (ii) genes never substituted (i.e., cold genes). The set of cold genes, which were 21% of the genes sequenced, were further winnowed down by examining excess expression levels. Both the most highly substituted genes and the most highly expressed never-substituted genes were biased in age toward the most ancient of genes. This would support the model that cancer represents a revision back to ancient forms of life adapted to high fitness under extreme stress, and suggests that these ancient genes may be targets for cancer therapy.
↵2Deceased June 5, 2015.
Author contributions: A.W., Q.Z., G.L., R.A.G., N.P., P.C.W.D., J.C.S., and R.H.A. designed research; A.W. and R.H.A. performed research; A.W., Z.K., R.A.G., K.B., and R.H.A. contributed new reagents/analytic tools; A.W., Q.Z., H.J.K., N.P., K.B., P.C.W.D., J.C.S., and R.H.A. analyzed data; and A.W., G.L., R.A.G., K.B., P.C.W.D., J.C.S., and R.H.A. wrote the paper.
Reviewers: E.B.-J., Tel Aviv University; and M.W.D., Rice University.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1512396112/-/DCSupplemental.
Freely available online through the PNAS open access option.
